DNA methylation and demethylation driven regulation of sepsis

Abstract

During dysregulated inflammation and sepsis, there is a sudden surge of cytokines, such as TNF alpha, IL6, and IL10, which disrupts the body homeostasis. This sudden and rapid increase in cytokine gene expression cannot be explained by the conventional central dogma mechanism. DNA methylation is one of the most significant epigenetic modifications. DNA methylation is mostly associated with the suppression of gene activity, and DNA demethylation is associated with the activation of gene activity. There are numerous transcription factors, such as CREB1, c-FOS, AP-1, IRF1, and EGR1, that play pivotal roles in regulating inflammation. Thus, it was hypothesized that changes in the DNA methylation patterns of cytokine promoter regions or in the promoter regions of these specific transcription factors might be the potential reasons for the increase in cytokine levels during sepsis. During endotoxin stimulation, DNA methyltransferases were suppressed, and DNA methylation levels were altered at the global level. Bisulfite sequencing revealed no change in the DNA methylation patterns of the TNF-alpha, IL6 and IL10 cytokine promoters. The CREB1 and c-FOS transcription factor promoters were demethylated after LPS stimulation and in clinical sepsis samples. Overall, this study highlights the importance of the role of DNA methylation in sepsis.